1. Field of the Invention
Beta-dihydrothebaine has the structural formula, ##STR1## is a member of the morphine alkaloid family in general, and is a derivative of thebaine in particular. Thebaine, a natural alkaloid, has the following structure: ##STR2## In formulas I and II, as elsewhere in this specification, a dashed line represents a covalent bond projecting below the plane of a reference atom while a wedged or heavily-accented line signifies a covalent bond projecting above such plane. Both .beta.-dihydrothebaine and thebaine are important intermediates in the synthesis of analgesic narcotic antagonist compounds. For a thorough review of the field, refer to: Bentley, K. W., The Chemistry of the Morphine Alkaloids, Chapters XII and XV, London, Oxford, 1954; and Bentley, K. W., "The Morphine Alkaloids", in: The Alkaloids, Vol. XIII, Manske, R.H.F. (Ed.), Chapter 1, New York, Academic Press, 1971.
2. The Prior Art
Schmid and Karrer (Helv. Chim. Acta, 33:873 [1950]; hereafter "Schmid") report that reduction of thebaine with LiAlH.sub.4 in benzene and ether results in a 42% yield of .beta.-dihydrothebaine.
Bentley, Lewis and Taylor (J. Chem. Soc., C, 1945 [1969]; hereafter "Bentley I"), however, find the Schmid reaction unsatisfactory: large amounts of thebaine remain unreacted even after the reaction proceeds for more than 48 hours; the process yields phenolic products othr than .beta. -dihydrothebaine; and the yield report in Schmid is not reproducible. Bentley I further describes the results of studies in the reduction of thebaine utilizing mixtures of LiAlH.sub.4 and AlCl.sub.3. Lithium aluminum hydride and aluminum chloride at respective ratios of 1:1, 1:3, or 1:4 provide neodihydrothebaine, ##STR3## as the major product; and traces of thebaine-A enol methyl ether, ##STR4## On the other hand, LiAlH.sub.4 and AlCl.sub.3 at respective ratios of 4:1 to 3:1 yield thebaine-A enol methyl ether, IV, as the principle product and traces of neohydrothebaine (III), .beta.-dihydrothebaine (II), and an unidentified C-4 phenolic compound.
Bentley, Robinson, and Main (J. Chem. Soc., 958 [1952]; hereafter "Bentley II") elucidate the structure of dihydrothebaine-.phi., ##STR5## and communicate that reaction of thebaine with sodium in liquid ammonia results in a 95% yield of dihydrothebaine-.phi. without trace of the .beta.-dihydrothebaine isomer.
Birch and Friton (Aust. J. Chem., 22:971 at 972 [1966]; hereafter "Birch") disclose that: "Reduction of thebaine with sodium in liquid ammonia opens the ether ring, but the resulting methoxycyclohexadine [i.e., dihydrothebaine-.phi.] has unconjugated double bonds which cannot be readily conjugated by the usual basic reagents. (emphasis supplied)." The Birch reference thus teaches that isomerization of dihydrothebaine-.phi. (V) to .beta.-dhydrothebaine (I) will not proceed with alkali metal amides in liquid ammonia.
Table A provides a synopsis of the preceding prior art. This analysis of the prior art thus indicates that there is no current simple, satisfactory method for producing .beta.-dihydrothebaine is reasonably good yields.
Table A __________________________________________________________________________ Summary of Reactions Disclosed by Prior Art Reference Starting Material Reactants Product __________________________________________________________________________ Schmid LiAlH.sub.4 .beta.-dihydrothebaine (42%)* LiAlH.sub.4 -- AlCl.sub.3 neodihydrothebaine (III) (1:1, 1:3, or 1:4) and trace of thebainone-A enol methyl ether (IV) Bentley I Thebaine (II) LiAlH.sub.4 -- AlCl.sub.3 neohydrothebaine (III) (4:1 or 3:1) and traces of .beta.-dihydro- thebaine (I) Bentley II Na -- liq NH.sub.3 dihydrothebaine-.phi. (V) Birch dihydrothebaine-.phi. Na -- liq NH.sub.3 None (V) __________________________________________________________________________ *Disputed by Bentley I